Neuropharmacology of Second-generation Antipsychotic Drugs: a Validity of the Serotonin-dopamine Hypothesis

Newer atypical antipsychotic drugs such as risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole that have been modelled on the prototype agent clozapine and developed since the 1990 s are now referred to as second-generation antipsychotic drugs (SGAs). It has been proposed that the interaction between serotonin (5-HT) and dopamine systems may play a critical role in the mechanism of action of atypical antipsychotic drugs because a relatively potent blockade of 5-HT(2A) receptors coupled with the weaker antagonism of the dopamine D(2) receptors is found to be the only pharmacological feature which most atypical antipsychotic drugs have in common. This so-called 'serotonin-dopamine hypothesis' has become a useful model for developing new SGAs to achieve superior antipsychotic efficacy with a lower incidence of extrapyramidal side effects compared to those with first-generation antipsychotic drugs (FGAs) such as haloperidol and chlorpromazine, although it has not been validated yet. In contrast, it has been proposed as the alternative 'fast-off' theory according to which atypical profile of SGAs can be determined by the loose D(2)-binding kinetics alone, while the blockade of the 5-HT(2A) receptor may be neither necessary nor sufficient. This chapter reviews the current issues on the serotonin-dopamine hypothesis together with further advances in research on the role of 5-HT receptor subtypes in the mechanism of action for SGAs. In particular, SGA-induced dopamine release in the prefrontal cortex, possibly through the functional activation of 5-HT(1A) receptors by 5-HT(2A) and D(2) receptor-mediated interaction, has been thought to be the basis for the neurocognitive effects of these drugs on schizophrenia. Thus, the novel antipsychotic aripiprazole may not only be a simply partial D(2) agonist but also a significant 5-HT(1A) agonist and 5-HT(2A) antagonist. These complex properties of antipsychotic aripiprazole may contribute to dopaminergic activation of the local circuitry in the prefrontal cortex of schizophrenic patients.